Insulin enhances the effect of nitric oxide at inhibiting neointimal hyperplasia in a rat model of type 1 diabetes

Varu, Vinit N.; Ahanchi, Sadaf S.; Hogg, Melissa E.; Bhikhapurwala, Hussein A; Chen, Amy; Popowich, Daniel A.; Vavra, Ashley K.; Martinez, Janet; Jiang, Qun; Saavedra, Joseph E.; Hrabie, Joseph A.; Keefer, Larry K.; Kibbe, Melina R.

doi:10.1152/ajpheart.01234.2009

Cited by 18 publications

(23 citation statements)

References 47 publications

(45 reference statements)

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“…The mechanism of arterial wall thickening associated with DM is not clear, because smooth muscle cells of the tunica media may increase in size as a result of hyperplasia or hypertrophy. Hyperplasia of the neointima associated with DM has been shown to result from smooth muscle cell proliferation in the tunica media and subsequent migration to the tunica intima, leading to vascular stenosis (26). This migration process did not occur in the current study, and there was no disruption of the internal elastic layer.…”

Section: Discussioncontrasting

confidence: 45%

Sinusoidal Constriction and Vascular Hypertrophy in the Diabetes-Induced Rabbit Penis

et al. 2013

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Objective: To assess the morphological changes of penile vascular structures and the corpus cavernosum area in alloxan-induced diabetic rabbits. Materials and Methods: Twenty male rabbits (2 months old) were divided into two groups with 10 rabbits each, the control group (CG) and the diabetic group (DG). The animals from DG received an intravenous injection of alloxan (100mg/kg) to induce the diabetes. Ten weeks after the induction of diabetes, all animals were euthanized. Two fragments of the penile shaft were harvested and samples were processed and paraffin embedded. Sections (5µm) were cut and stained for histological and immunohistochemical markers. Results: Nuclear protrusion toward the lumen, and cytoplasmic vacuolization were observed in the tunica intima of the dorsal artery of the penis in DG. The thicknesses of the tunica media increased significantly in DG (p = 0.0350). It was also observed a significant increase in the area of the tunica media (p = 0.0179). There was no significant change in smooth muscle cell density in the tunica media of the dorsal artery of the penis (p = 0.0855). The collagen fiber pattern of the tunica adventitia of the dorsal artery of the penis was different between the control and diabetic groups. There was a significant decrease in the area occupied by the cavernous sinuses in DG (p = 0.0013). Conclusion: Alloxan-induced diabetes mellitus in rabbits promotes important changes in penile vascular structures, thereby decreasing blood supply and affecting penile hemodynamics, leading to erectile dysfunction.

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Section: Discussioncontrasting

confidence: 45%

Sinusoidal Constriction and Vascular Hypertrophy in the Diabetes-Induced Rabbit Penis

et al. 2013

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“…This is the same dose of PROLI/NO that was used in our prior studies. [20,21] Treatment groups for all STZ and ZDF group assignments included: 1) injury, and 2) injury+PROLI/NO (n=6–7/treatment group). Carotid arteries were harvested 14 days after injury for morphometric analysis.…”

Section: Methodsmentioning

confidence: 99%

“…[20] However, with the addition of insulin, the efficacy of NO was restored in type 1 diabetic rats. [21] Yet, with these studies, the effect of NO in a controlled type 1 or type 2 diabetic environment was not determined. It is unclear whether the hyperinsulinemia and/or hyperglycemia are responsible for regulating the efficacy of NO in these diabetic environments.…”

Section: Introductionmentioning

confidence: 97%

Role of metabolic environment on nitric oxide mediated inhibition of neointimal hyperplasia in type 1 and type 2 diabetes

et al. 2014

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Nitric oxide (NO) is well known to inhibit neointimal hyperplasia following arterial injury. Previously, we reported that NO was more effective at inhibiting neointimal hyperplasia in a type 2 diabetic environment than control. We also found that NO was ineffective in an uncontrolled type 1 diabetic environment; however, insulin restored the efficacy of NO. Thus, the goal of this study was to more closely evaluate the effect of insulin and glucose on the efficacy of NO at inhibiting neointimal hyperplasia in both type 1 and type 2 diabetic environments using different doses of insulin as well as pioglitazone. Type 1 diabetes was induced in male Lean Zucker (LZ) rats with streptozotocin (60mg/kg IP). Groups included control, moderate glucose control, and tight glucose control. Zucker Diabetic Fatty (ZDF) rats fed Purina 5008 chow were used as a type 2 diabetic model. Groups included no therapy, insulin therapy, or pioglitazone therapy. After 4 weeks of maintaining group assignments, the carotid artery injury model was performed. Treatment groups included: control, injury, and injury plus NO. 2 weeks following arterial injury, in the type 1 diabetic rats, NO most effectively reduced the neointimal area in the moderate and tightly controlled groups (81% and 88% vs. 33%, respectively, p=0.01). In type 2 diabetic rats, the metabolic environment had no impact on the efficacy of NO (81%–82% reduction for all groups). Thus, in this study, we show NO is effective at inhibiting neointimal hyperplasia in both type 1 and type 2 diabetic environments. A greater understanding of how the metabolic environment may impact the efficacy of NO may lead to the development of more effective NO-based therapies for patients with diabetes.

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“…The importance of NO to ensure the correct function of VSMC and avert the onset of atherosclerosis is proven by a number of experimental studies in vitro and in vivo. In a cellular model of atherosclerosis, insulin-stimulated NO production limits VSMC migration (82) and prevents intima hyperplasia (155). Interestingly, increased expression of endothelial NO synthase at plaque level has been demonstrated in patients with acute coronary syndrome rather than in patients with stable angina (135), further suggesting that NO production may have a pivotal role in plaque progression.…”

Section: Molecular and Cellular Properties Of Rosiglitazonementioning

confidence: 99%

Determinants of evolving metabolic and cardiovascular benefit/risk profiles of rosiglitazone therapy during the natural history of diabetes: molecular mechanisms in the context of integrated pathophysiology

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et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Rosiglitazone is a thiazolidinedione, a synthetic PPARγ receptor agonist with insulin-sensitizing properties that is used as an antidiabetic drug. In addition to improving glycemic control through actions in metabolic target tissues, rosiglitazone has numerous biological actions that impact on cardiovascular homeostasis. Some of these actions are helpful (e.g., improving endothelial function), whereas others are potentially harmful (e.g., promoting fluid retention). Since cardiovascular morbidity and mortality are major endpoints for diabetes, it is essential to understand how the natural history of diabetes alters the net benefits and risks of rosiglitazone therapy. This complex issue is an important determinant of optimal use of rosiglitazone and is critical for understanding cardiovascular safety issues. We give special attention to the effects of rosiglitazone in diabetic patients with stable coronary artery disease and the impact of rosiglitazone actions on atherosclerosis and plaque instability. This provides a rational conceptual framework for predicting evolving benefit/risk profiles that inform optimal use of rosiglitazone in the clinical setting and help explain the results of recent large clinical intervention trials where rosiglitazone had disappointing cardiovascular outcomes. Thus, in this perspective, we describe what is known about the molecular mechanisms of action of rosiglitazone on cardiovascular targets in the context of the evolving pathophysiology of diabetes over its natural history.

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Insulin enhances the effect of nitric oxide at inhibiting neointimal hyperplasia in a rat model of type 1 diabetes

Cited by 18 publications

References 47 publications

Sinusoidal Constriction and Vascular Hypertrophy in the Diabetes-Induced Rabbit Penis

Sinusoidal Constriction and Vascular Hypertrophy in the Diabetes-Induced Rabbit Penis

Role of metabolic environment on nitric oxide mediated inhibition of neointimal hyperplasia in type 1 and type 2 diabetes

Determinants of evolving metabolic and cardiovascular benefit/risk profiles of rosiglitazone therapy during the natural history of diabetes: molecular mechanisms in the context of integrated pathophysiology

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